It is well known that many diverse human diseases such as cancer, dementia, or decreased cognitive functioning increase in incidence with age. From an epidemiological and statistical perspective, these diseases often look very similar. However, from a clinical perspective, each of the cancers, dementias, and decreased cognitive functioning are very different. Currently, the largest risk factor for these disorders is the subject's age. Furthermore, it is well established that most cancers, dementias, and decreased cognitive functioning have a long prodromal phase (5-15 years) in which the disease is present but at a sub-clinical manifestation. Age-associated increases in membrane cholesterol1-3 and increased mitochondrial membrane cholesterol4-6 have been reported. These increases in membrane cholesterol result in decreased membrane fluidity2, decreased ion channel function6-8, decreased activities of some membrane-bound enzymes like 5′-nucleotidase9 and α-secretase10, and altered diffusion properties for signaling molecules like nitric oxide11.
Subjects suffering from increased membrane cholesterol demonstrate an increased prevalence of neurodegenerative diseases (e.g. Alzheimer's, Parkinson's, multiple sclerosis and age-related macular degeneration), cognitive impairment, dementia, cancers (e.g. prostate, lung, breast, ovarian, and kidney), osteoporosis, bipolar disorder and vascular diseases (atherosclerosis, hypercholesterolemia).
With respect to specific diseases, cholesterol accumulates in the brain membranes of Alzheimer's patients in a severity-dependent manner12-14. In this regard, lowering membrane cholesterol has been shown to decrease the activities of beta- and gamma-secretases, blocking the pathogenic processing of beta-amyloid15-16. At the molecular level, cholesterol binds to the transmembrane domain of amyloid precursor protein (APP), activating the trafficking of APP to cholesterol-rich membrane domains rich in beta- and gamma-secretases, resulting in amyloid-beta production17. Synaptic membrane changes resulting from increased cholesterol may also be an important factor in the utilization of membrane phospholipids to support cholinergic neurotransmission (autocannibalism concept)18. Early utilization of statins have also been suggested to reduce the incidence or delay the onset of Alzheimer's and Parkinson's diseases19. Cholesterol accumulation also occurs in the drusen associated with age-related macular degeneration20. Membrane cholesterol is also increased in cancer21 and increases in mitochondrial membrane cholesterol have been hypothesized to be the defect that leads to the Warburg effect that is associated with most cancer cells22. The Warburg effect is a defining feature of cancer cells in that, unlike normal cells, which rely almost entirely upon respiration for energy, cancer cells can utilize both respiration and glycolysis for energy.
In addition to complex negative membrane effects of cholesterol accumulation, there is also increased oxysterol production23. These oxysterols are cytotoxic (apoptosis and necrosis), pro-inflammatory, deplete GSH and induce phospholipidosis23-26. Diseases in which these toxic oxysterols might be involved include neurodegeneration (both neuronal and demyelinating), osteoporosis, age-related macular degeneration and cardiovascular diseases, particularly atherosclerosis23.
Current clinical therapies to reduce cholesterol consist mainly of inhibiting cholesterol synthesis with statins or blocking cholesterol absorption from the gastrointestinal tract with ezetimibe. To the inventors' knowledge, there are currently no drugs to mobilize cholesterol trafficking out of membranes.